Author Information

We appreciate very much the letters received regarding the STOP AF trial (North American Arctic Front). This correspondence has provided thoughtful considerations regarding ablative intervention in general, and the cryoballoon STOP AF Trial (1) in specific. In terms of safety issues, it is important to reiterate that we elected to include each and every adverse event that occurred over the course of the 12 months of the trial. Although a single tamponade and infarction episode occurred at the time of the intervention, the fatal myocardial infarction occurred at 11 months of follow-up and was unrelated to the ablative intervention. Of the 5 events reported as strokes, 1 was related to the ablative intervention in a patient crossing over from drug therapy. The other 4 events occurred at 183, 51, 30, and 260 days after ablation and were not procedure related. Such late complications are not typically reported in other trials, but were included in STOP AF for completeness.

Phrenic nerve injury is a significant complication of cryoablation occurring in 11.2%. In contrast, in the STOP AF Continued Access Protocol (CAP AF), phrenic nerve palsy (PNP) occurred in 3 procedures (3 of 85, 3.5%), with complete resolution in all 3 of the subjects by the end of follow-up (2). This decrease in occurrence is in part because of the increased experience of the operators, and therefore reflects early “real world” experience.

The definition of pulmonary vein (PV) stenosis, with a > 75% reduction in cross-sectional area (approximately a 50% reduction in diameter) used in the trial is nonstandard (3,4). The use of “area” overestimates the severity of stenosis. A reanalysis of the STOP AF data using a 70% diameter reduction shows that only 6 of 905 cryoablated veins (0.7%) exceeded this criterion (2). Nevertheless, there were 2 serious stenoses during the trial, one of which required intervention, although the other subject refused. The management of patients with PV stenosis otherwise followed typical approaches used in the United States and Europe (3,4). In our experience with PV stenosis, we have found perfusion scans to be of limited value, although they identify a decrement in perfusion in those patients with > 65% stenosis (3). We have no experience with bodyplethysmography, nor has this been included in any prior report of pulmonary vein stenosis or postablation phrenic nerve injury of which we are aware. This may be an interesting topic for a later observational study.

Based on these issues addressed in the original STOP AF manuscript and clarified here, we believe that the safety endpoints of the trial were appropriately met and reported (1). The safety and efficacy outcomes of the STOP AF trial are also consistent with the recent THERMOCOOL Ablation Study (5) and those from MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) (6) and RAAFT 2 (First Line Radiofrequency Ablation versus Antiarrhythmic Drugs for Atrial Fibrillation: A Multicenter Randomized Trial) (7). Additional clinical trials will be required to establish the long-term efficacy and safety of AF ablation in patients with underlying disease, advanced age, and more persistent AF: CABANA (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) (NCT00911508); EAST (Early Treatment of Atrial Fibrillation for Stroke Prevention) (NCT01288352); ATTEST (Atrial Fibrillation Progression Trial) (NCT01570361).

Several questions were raised in the second letter. In this trial, there were several patients with “early persistent AF”–defined as having undergone a single prior cardioversion–included as allowed in the Food and Drug Administration (FDA)-approved protocol. The letter correctly identified that 21 patients had a history of coronary artery disease, although none had a previous myocardial infarction.

With regard to the question about antiarrhythmic drug use, the 82 patients randomized to antiarrhythmic drug therapy were treated with an approved AF treatment drug—propafenone, flecainide, or sotalol—that they had not previously failed. The use of dofetilide and amiodarone were precluded by the U.S. FDA as a condition of study approval. Had these been available, the overall drug response rate may have been higher, although these are similar to the outcome of drug RX in early randomized AF ablation studies (5). There were, however, 13 cryoablated patients treated with an antiarrhythmic drug that had been previously ineffective, without any additional AF after the ablation, thus meeting efficacy criteria as specified by the protocol.

We agree with the impact of experience. Even in the STOP AF Continued Access Protocol, outcomes were better after an increment in experience (2). As indicated in the current publication, the STOP AF investigators used this approach without extensive prior experience, although the STOP AF efficacy outcome is not significantly different from the original reports coming from Europe and other US clinical trials (1). The ongoing additional experience does demonstrate shorter procedure times, and in part, a 30-min trial-specified waiting period in STOP AF.

We appreciate the commentary regarding approaches to avoiding phrenic nerve injury. Although we agree this complication is more likely to occur with smaller cryoballoons, we believe it is critically related to the relationship between the cryoballoon and pulmonary vein size. A 23-mm balloon may be appropriate in patients with small veins. Obviously a 23-mm balloon used in a large vein contributes to the occurrence of both phrenic nerve injury and PV stenosis as has been previously established.

Several studies have demonstrated that the outcome with cryoballoon ablation in patients with persistent AF and those with significant underlying disease is anticipated to be less effective (8,9). In addition, the single procedure success rate is most appropriately compared with the early experience with this balloon system, rather than recent reports of extended experiences. The efficacy rates are also similar to recent trials examining RF ablation of AF (5). The combination of the STOP AF trial with these data demonstrate an acceptable trajectory as additional experience is acquired. Additional details regarding minimal temperatures reached, the predictors of success and failure, and the overall temperature dependence of cryoablation will be the topics of subsequent manuscripts.

Finally, as indicated, 31 patients underwent repeat cryoballoon ablation during the blanking period. Each of these had reconnection of their PVs. One can argue that a longer blanking period might have demonstrated resolution of recurrent AF in some patients. Nevertheless, at the time of enrollment in this trial, a 3-month blanking period was standard. In subsequent trials, it will be a testable hypothesis that waiting a longer period of time after ablation might disclose higher success rates than seen with current approaches. Additional studies comparing current and emerging technology will require additional consideration.

We are pleased with the opportunity to respond to these questions, and hope that this allows further clarity of presentation. We remain convinced that the STOP AF study is a very transparent presentation of the safety and efficacy outcomes of AF cryoballoon ablation, and look forward to additional randomized clinical trials comparing it with PV isolation using RF energy.

Toolbox

Thank you for your interest in spreading the word about JACC: Journal of the American College of CardiologyNOTE: We request your email address only as a reference for the recipient. We do not save email addresses.

Your Email *

Your Name *

Send To *

Enter multiple addresses on separate lines or separate them with commas.